This invention relates to a drug for preventing and treating AIDS which contains as its effective component a Fas antagonist which suppresses apoptosis induced by Fas--Fas ligand system, and in particular, an anti-Fas ligand antibody.
Fas is a cell surface antigen which transmits apoptosis signal to the cell, and Fas is recognized by Fas antibody (Yonehara, S. et al., J. Exp. Med. vol. 169, 1747-1756, 1989) which is a monoclonal antibody produced by immunizing a mouse with human fibroblast.
Human Fas ligand is a polypeptide which has been reported by Nagata et al. to be a biological molecule which induces apoptosis of Fas-expressing cells (Takahashi, T. et al., International Immunology, vol. 6, 1567-1574, 1994). Human Fas ligand is a Type II membrane protein of TNF family with a molecular weight of about 40 kD. As in the case of TNF, human Fas ligand in the human body is estimated to be in the form of a trimer (Tanaka, M. et al., EMBO Journal, vol. 14, 1129-1135, 1995). The extracellular domain of the human Fas ligand is highly homologous with the extracellular domain of rat Fas ligand (Suda, T. et al., Cell, vol. 75, 1169-1178, 1993) and mouse Fas ligand (Takahashi, T. et al., Cell, vol. 76, 969-976, 1994). The human Fas ligand recognizes not only the human Fas but also the mouse Fas to induce the apoptosis, and vice versa, the rat Fas ligand and the mouse Fas ligand also recognize the human Fas to induce the apoptosis.
Considerable researches have also been done on the mechanism of signal transduction in the cell upon the Fas-mediated apoptosis, and identification and cloning of the factor which interacts with the intracellular domain of the Fas, in particular, the region called "death domain" to transmit or block the signal have been reported. Possibility of the involvement of ICE (interleukin-1-converting enzyme)-related thiol proteases in the Fas-mediated apoptosis has also been indicated.
Acquired immune deficiency syndrome (AIDS) is a condition wherein human immunodeficiency virus (HIV) has targeted and infected CD4.sup.+ T lymphocytes and the destruction of the CD4.sup.+ T lymphocytes has induced serious immunodeficiency. AIDS is the terminal condition of the HIV infection subsequent to the asymptomatic stage and the following stage of various immunodeficiency symptoms. The term, HIV infection is a generic term including all of such stages.
Destruction of the CD4.sup.+ T lymphocytes inviting the onset of the AIDS has been formerly estimated to be the immediate result of the cell destruction by the HIV infection and virus propagation. Recent studies, however, have indicated the relation of the apoptosis with the decline in number of the CD4.sup.+ T lymphocytes. Kobayashi, N. (Jikken Igaku (Experimental Medicine), vol. 13, No. 16, 1981-1988, 1995) has reported that lymphocytes of the peripheral blood collected from patients suffering from HIV infection exhibit a Fas expression rate higher than that of the normal donor, and that the apoptosis is induced by the Fas stimulation in such lymphocytes in a period shorter than the normal donor. Okamoto, M. et al. (Igaku Kensa (Medical Tests), vol. 45, No. 12, 1693-1698, 1996) has proposed a possible mechanism for the decline in the number of T cells in the HIV infection that, in the case of the HIV infection, uninfected CD4.sup.+ T cells are activated to express the Fas, and the thus expressed Fas interacts with the Fas ligand from the HIV-infected monocytes or macrophages to induce the apoptosis. Nakanishi, Y. (Jikken Igaku (Experimental Medicine), vol. 15, No. 19 (Special Issue), 2449-2453, 1997), however, has reported that T lymphocytes of the peripheral blood collected from those suffering from HIV infection undergoes apoptosis even if macrophages were absent.
Estaquier, J. et al. (Blood, vol. 87, No. 12, 4959-4966, 1996) has demonstrated that the apoptosis induced by interacting the soluble Fas ligand with the CD4.sup.+ T cells or CD8.sup.+ T cells separated from the lymphocytes of the peripheral blood collected from those suffering from HIV infection could be suppressed by antagonistic anti-Fas antibody or Fas-Fc fusion protein. Yang, Y. et al. (Blood, vol. 89, No. 2, 550-557, 1997) has reported that in vitro spontaneous cell death of the lymphocytes of the peripheral blood collected from those suffering from HIV infection could be suppressed by Fas-Fc fusion protein.
HIV infection has been treated by using various reverse transcriptase inhibitors and/or protease inhibitors which are capable of inhibiting virus propagation. Such treatments often invited adverse actions such as vomiting, vomiturition, softening of feces, diarrhea, hepatopathy, pancreas damage, myelosupression, and among others, anemia and decline in the number of white blood cells, and such adverse actions were often quite serious. In addition, occasional appearance of the virus exhibiting resistance to such agents in the course of the treatment has made the treatment of the HIV infection quite difficult.
No suggestion has so far been made for the action of the transcriptase inhibitor or the protease inhibitor to suppress the apoptosis induced by the Fas--Fas ligand system which is responsible for the decline of T lymphocyte count in the HIV infected patient.
Use of an HIV neutralizing antibody for the treatment of the HIV infection has been proposed in Published Japanese Translation Nos. 3-504556 (WO 88/09181), 9-505466 (WO 95/11317), JP-A 6-217791 (WO 93/19785), and the like. The virus neutralizing antibody is expected to bind to the virus released from the infected cell to neutralize the infectivity of the virus, and effectivity of the virus neutralizing antibody in preventing the infection by HIV has been demonstrated in the infection experiment using chimpanzees as described in JP-A 6-217791 (WO 93/19785). The HIV neutralizing antibody, however, would not be suitable for use in the removal of the infected T cells, and virus surface antigens are also known to undergo mutations which results in reduced binding with the antibody. In addition, there has so far been no indication for the HIV neutralizing antibody to suppress the apoptosis induced by the Fas--Fas ligand system which is one of the mechanisms for the decline of T lymphocyte count in the HIV infected patient.
JP-A 2-237935 discloses that growth of the HIV-infected cell line had been suppressed in an in vitro experiment by the anti-Fas antibody (agonistic anti-Fas antibody) which induces apoptosis by binding to Fas on the cell surface. JP-A 2-37935 also proposes a drug for treating AIDS containing such agonistic anti-Fas antibody. WO 97/12632 discloses use of the Fas ligand or the agonistic anti-Fas antibody for promoting the apoptosis in the treatment of virus infections caused by HIV or herpes simplex virus (HSV)-2. Such induction of apoptosis of the HIV-infected cells by using the agonistic anti-Fas antibody is associated with the risk of simultaneous induction of apoptosis of the HIV-uninfected Fas.sup.+ CD4.sup.+ T cells, inviting further decline of the CD4.sup.+ T cell count in the HIV-infected patients to worsen the disease conditions.
WO 95/13293 (EP 675200) and WO 96/29350 proposes treatment of AIDS, hepatitis and rheumatism by using the anti-Fas ligand antibody. WO 97/02290 (PCT/JP96/01820) which is the parent application of the present application proposes use of the anti-Fas ligand antibody for the inhibition of the apoptosis by the Fas--Fas ligand system in the diseases which are expected to be associated with excessive apoptosis such as autoimmune diseases (rheumatism, SLE, and diabetes), virus infections (influenza and AIDS), hepatitis, rejection in organ transplantation, graft versus host disease, ulcerative colitis, Crohn's disease, and the like.
It is, however, not yet clear whether the Fas--Fas ligand system in the case of HIV infection is involved in the mechanism of removal of the HIV-infected cells or in the mechanism of death of the T cells. In the former case, hyperfunctioning of the Fas--Fas ligand system would be desirable in contrast to the latter case wherein the inhibition of the Fas--Fas ligand system is desirable. There is no specific report with regard to the effectivity of the anti-Fas ligand antibody for the HIV infection. In addition, Okumura, K. et al. (1997 Project for Promoting the AIDS Pharmaceuticals Development, International Research Grant Project, Research Report, 113-122, 1997) has reported that the anti-Fas ligand antibody failed to block anti-CD3 antibody-induced apoptosis of CD4.sup.+ T cells or CD8.sup.+ T cells from HIV-infected individuals, and indicated the presence of a mechanism other than the one involving the Fas--Fas ligand system for the apoptosis of T cells in the patients suffering from the HIV infection.
Published Japanese Translation Nos. 8-511692 (WO 95/27735) and 9-503672 (WO 95/10540) describe an inactivated Fas ligand analogue and antagonistic anti-Fas antibody as apoptosis inhibitory substances involving the Fas--Fas ligand system other than the anti-Fas ligand antibody. These publications, however, also fail to specifically refer to the HIV infection.
Effectivity of a prophylactic or therapeutic agent for AIDS can not be evaluated solely by in vitro experiments. For example, interleukin-2 is known to have an in vitro ability to proliferate the lymphocytes of peripheral blood collected from the patient infected with HIV. Kovacs, J. A. et al. (N. Engl. J. Med., vol. 332, No. 9, 567-575, 1995) administered the interleukin-2 to the patents infected with HIV. Increase in the CD4.sup.+ T cells was observed in some of the patients while further virus activation as well as drug adverse actions were observed in most of the patients with no immunological improvement. The results expected from the in vitro results were not at all reproduced in the in vivo experiment.
An object of the present invention is to provide a drug for preventing and treating HIV infection which prevents the decline of lymphocyte count by inhibiting the Fas antigen-mediated apoptosis. Another object of the present invention is to provide a method for preventing and treating HIV infection by utilizing such a drug. More specifically, the object of the present invention is to provide a drug for preventing and treating AIDS which contains as its effective component anti-Fas ligand antibody.